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Vol. 61, Issue 2, 312-319, February 2002

Phosphorylation of Blood Vessel Vasodilator-Stimulated Phosphoprotein at Serine 239 as a Functional Biochemical Marker of Endothelial Nitric Oxide/Cyclic GMP Signaling

César Ibarra-Alvarado, Jan Galle, Volker O. Melichar, Alexander Mameghani, and Harald H. H. W. Schmidt

Rudolf-Buchheim-Institute for Pharmacology, Justus-Liebig-University, Giessen, Germany (C.I.A., H.H.H.W.S.); Departments of Pharmacology and Toxicology (C.I.A., V.O.M.) and Medicine/Nephrology (J.G., A.M.), Julius-Maximilians-University, Würzburg, Germany; and Faculty of Chemistry, University of Querétaro, Centro Universitario, Querétaro, México (C.I.A.)

The endothelium-derived relaxing factors nitric oxide (NO) and prostacyclin (PGI2) are important antithrombotic, relaxant, and antiproliferative agents of the blood vessel wall that exert their intracellular effects primarily via cGMP- and cAMP-dependent protein kinases (cGK, cAK). However, no biochemical marker for their activity in the intact blood vessel is available except for transient increases in the concentration of cGMP and cAMP. Using Western blot analysis and specific antibodies, we show here that phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser239 (PSer239-VASP) in rabbit aorta was detectable only in segments with an intact endothelium, although at least one third of VASP is contained in the remaining vascular wall. In endothelium-denuded aorta, VASP phosphorylation was increased by the NO donor sodium nitroprusside (SNP). Levels of PSer239-VASP, in the presence of endothelium and either SNP or 8-bromo-cAMP, were maximal. VASP phosphorylation elicited by 8-bromo-cAMP was inhibited significantly by the cGK inhibitor Rp-8-Br-PET-cGMPS. Stimulated PSer239-VASP formation was fully reversible, reaching basal levels after 10 min of repeated washouts. Consistent with the important role that the NO/cGMP pathway plays in the formation of PSer239-VASP in rabbit aorta, inhibition of NO synthase by Nomega -nitro-L-arginine methyl ester (L-NAME; 1 mM) or of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[3,4-a]quinoxalin-1-one (ODQ; 50 µM) almost completely abolished PSer239-VASP formation in endothelium intact blood vessels. These data suggest that vascular PSer239-VASP is primarily regulated by the NO/cGMP pathway and may thus serve as a biochemical marker for the activity state of this essential pathway in endothelial function.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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